Amphetamine derivatives

ABSTRACT

DERIVATIVES OF AMPHETAMINE OBTAINED BY THE REACTION OF AMPHETAMINE WITH 2-ACYLLACTONE OR A B-KETO-ESTER OR THE COMPOUND OBTAINED UPON HYDROGENATION OF THE LACTONE REACTION PRODUCT ARE POTENT APPETITE DEPRESSANTS BUT DO NOT SHOW THE CNS ACTIVITY OF AMPHETAMINE.

United States Patent 3,576,009 AMPHETAMINE DERIVATIVES Ernest Magnien, Flushing, and Bill Elpern, White Plains, N.Y., assignors to USV Pharmaceutical Corporation No Drawing. Filed Apr. 2, 1968, Ser. No. 718,220 lint. Cl. C0711 5/ 06' US. Cl. 260343.6 5 Claims ABSTRACT OF THE DISCLOSURE Derivatives of amphetamine obtained by the reaction of amphetamine with 2-acyllactone or a B-keto-ester or the compound obtained upon hydrogenation of the lactone reaction product are potent appetite depressants but do not show the CNS activity of amphetamine.

This invention relates to new organic compounds having valuable pharmacological activity and to processes for the preparation of said compounds. In particular the invention relates to derivatives of amphetamine and amphetamine-like compounds.

Amphetamine is a potent anorexic agent and is used as such in cases of obesity. However, in addition to its anorexic activity amphetamine also has central nervous system stimulatory activity which is undersirable when patients are treated for obesity.

It is, accordingly, an object of this invention to provide derivatives of amphetamine or amphetamine-like compounds which possess the desirable anorexic properties but show little or no central nervous system stimulation. I

We have now found that derivatives of amphetamine and amphetamine-like compounds having the formula wherein m is or 1 R is hydrogen, lower alkyl, halogen or lower alkoxy,

R is hydrogen or hydroxy,

R is hydrogen, lower alkyl or phenyl-lower alkyl,

R, is hydrogen or lower alkyl,

R is radical of the formula R O CCH=C(R wherein R is lower alkyl and R is lower alkyl, or a a lactone of the fomula RE (A) wherein R is hydrogen, lower alkyl or phenyl, and R is hydrogen, lower alkyl, phenyl, lower alkoxymethyl, or phenoxymethyl, and n is an integer having the value of 24,

are potent anorexic agents but have little or no central nervous system stimulating activity.

The lower alkyl groups contain from 1 to 5 carbon atoms and include such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, amyl, isoamyl and the like. The lower alkoxy groups contain from 1 to 5 carbon atoms and include such groups as methoxy, ethoxy, iso propoxy, butoxy, and the like.

Preferably n is 2, m is 1, R is hydrogen or methoxy, R is hydrOgen, R is lower alkyl, R, is hydrogen, R is ethyl, R is methyl, R is hydrogen, and R is methyl.

Where R is a lactone of structure A the compounds are prepared by contacting at ambient temperature in the presence of an inert solvent, such as benzene, toluene, hexane, chloroform, chlorobenzene and the like, an amine of the formula with an appropriately substituted 2-acyl-lactone of the formula The lactone compounds of structure B are readily obtained by the hydrogenation of the double bond in the lactone of structure A.

To obtain the ring-substituted acyl-lactones, an appropriately substituted 1,2-epoxide is reacted with the sodium salt of ,B-keto-ester.

Where R is the R O CCH C(R group, the compound is obtained by the reaction of the amine above with a [i-keto ester of the formula under conditions similar to those above.

In these processes the product is obtained in crude form upon evaporation of the inert solvent and is then purified by crystallization.

In the above formulas R to R have the same meaning as previously described.

The invention will be more fully understood from the examples which follow, and it is intended to cover all changes and modifications of the invention herein chosen for purposes of disclosure which do not constitute departures from the spirit and scope of the invention.

EXAMPLE 1 d-2- (Z-hydroxyethyl -3 1-phenyl-2-propyl-amino) crotonic acid lac-tone To a solution of 200 g. (1.485 mole) of d-amphetamine in 200 ml. of benzene is added 190 g. (1.485 mole) of 2- acetylbutylrolactone. After 18 hrs., the benzene solution is decanted from the separated water and dried over MgSO The benzene is removed in vacuo and the resulting oil is crystallized from ether to yield 187 g. (51.5%) of crude product. A further crystallization from ether results in 107 g. of pure product of MP. 64-67".

EXAMPLE 2 (a) 2-acetyl-4-phenoxymethylbutyrolactone To a solution of 11.5 g. (0.5 mole) of sodium in 200 ml. of dried ethanol was added at 50, 65 g. (0.5 mole) of ethylacetoacetate. To this solution was added g. (0.5 mole) of 1,2-epoxy-3-phenoxypropane. The mixture was allowed to stand for 40 hours. 30 g. (0.5 mole) of acetic acid and 100 ml. of water was added with cooling and the resulting oil was extracted into ether. Evaporation to a small volume and cooling resulted in crystals of the product of M.P. 7073. Recrystallization from ethyl acetate- The anorexic activity and CNS activity in dogs of representative compounds are shown in Table II.

hexane gave pure material of MP. 72-73". 5 TABLE H (b) d-2- 2-hydroxy-3-phenoxypropyl -3-( l-phenyl- Minimal 2-propylamino)-crotonic acid lactone CNS No.01 compound in Table E.R.D.5O stmnlgbgg A mixture of 20 g. (0.085 mole) of 2-acetyl-4-phenv or example (High/kg (nigh/kg) oxyrnethylbutyrolactone and 7.7 g. (0.057 mole) of d- 10 I N amphetamine in 100 ml. of benzene was allowed to stand f; 2:8 at room temperature for 60 hours. A colorless solid ap- Example III n 5.8 peared 10 min. after mixing, but redissolved after standg'i ib 'fj 3:3 ing. The solution was refluxed for /2 hour and then dismm 4.0 5.0 tilled to yield 16.8 g. of material having a HP. of 250- m0 260/O.2 mm. and an 21, 1.5920. nun-50 is the Effective Refusal D0se-dose at which one-half of the animals refuse to eat. EXAMPLE 3 Ethyl 3-( 1-methyl-2-phenethylamino) -crotonate The compounds herein described may be administered A mlxture of of d'amphetamme and of orally in the form of tablets, capsules, elixirs, solutlons, ethyl acetoacetate ll! 20 ml. of xylene was refluxed for 4 and the mm The Compounds may be taken in dosages hours with removal of water m a Dean Stark trap. After totaling from 5 to 50 mg/kg daily evaporation of the xylene, the fSlClllE was dlSt12l5l6Cl to yield The individual i dosages and frequency of deterof Product of 128 /O'O3 mination will be determined by the subjects Weight, age

EXAMPLE 4 and indulgency, physical condition, and it will be within the professional judgment of the practitioner administering 3-(l,3-diphenyl-2-propylamino)-2-(2-hydroxythe drug to determine the exact amount to be adminisethyl) crotonic acid lactone tered. We claim:

A solution of 15 g. of 1,5-d1phenyl-2-ammopropane A Compound of the formula (prepared by L1AlI-I reduction of the corresponding oxime) and 9.1 of Z-acetyl-butyrolactone in 20 ml. of benzene was refluxed for 4 hours with removal of water. CHR' (CHR) The product was distilled after removal of the solvent to J yield 20.7 g. of material of BF. 210-215 /0.()5 mm. To s this material was added 20 ml. of ether and a colorless solid was filtered oflf. The filtrate was treated with 80 ml. RI of hexane and the product which precipitated was filtered oil. Recrystallization from ether-hexane resulted in a 40 wherein product of MP. 63-65. m is O or 1,

R is hydrogen, lower alkyl, halogen, or lower alkoxy, EXAMPLE 5 R is hydrogen or hydroxy, 2-(hydroxyethyl)-3-d-(l-phenyl-2-propy1amino)- a hydfogen, lower alkyl or p y alkyl,

butyric acid lactone R 18 hydrogen or lower alkyl, and

R is a lactone of the formula A solution of g. d-2-(2-hydroxy-ethyl)-3-(-phenyl- 2-propylamino) crotonic acid lactone in 250 ml. of ethanol CHCH(R Was placed in a Paar hydrogenerator with 1 g. of platinum (CHM oxide and shaken for 24 hours at an initial pressure of 50 18.6 lbs/sq. in. After 24 hours, an additional 1 g. of Rs OC=C platinum oxide was added and shaking was resumed for r 11 hours. After removal of the spent catalyst the solution 0 was evaporated and the residue was distilled to yield 35 g. of product of BF. l62'l64/0.05 mm, n 1.5635. The (CH2)2 maleate salt has an M.P. of 109-112".

Following similar proceduces, the following additional R8 0C=O compounds were prepared:

TABLE I fm=1, 'n=2, R5=A R1 R2 R3 R4 R1 R8 M1. or 13.1

Compound No.:

1 H H CH3 ((11) H OH; H 8384". H H H CH3 H s0-s3. H OH; H CH3 H SEE-85. H CH3 H CH3 H (MW/0.05 mm). H CH3 H CH3 H s7-ss. H CH3 H CH3 H 85-87"- 0H CH: 11 CH; H 186-188". H OH; H 03H? H (UT/0.08 111.111.). H CH3 H 06115 H 103-104. H CH3 H CH; CH; (1s0-1se/0. 02 mm.). H CH3 H CH1 C6115 (23a-242 0.2 mm.). C2H5 CH3 H CH3 H (l68/0.07 mm.) H H3 CH3 CH3 H aw/0.3 mm.). H Cm H CH3 H (176178/0.2 mm.). H CH3 H CH3 H 78-79.

wherein R is hydrogen, lower alkyl or phenyl, and R is hydrogen, lower alkyl, phenyl, lower alkoxymethyl,

or phenoxymethyl. 2. A compound according to claim 1, wherein m is 1, R is hydrogen, R is hydroxy, R is methyl, R is hydrogen, and R is of the structure C=C(CHa)- (CH2):

OC=O

3. A compound according to claim 1, wherein m is 1, R is hydrogen, R is hydrogen, R is methyl, R, is hydrogen, and R is of the structure 5. A compound according to claim 1 wherein m is 1, R is hydrogen, R is hydrogen, R is methyl, R is hydrogen, and R is of the structure CHCH(GH3) OC=O References Cited UNITED STATES PATENTS 3,274,248 9/1966 Harsnyi et a1 260-343.6

ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner US Cl. X.R. 

